Broadly this project's goals are to better understand the neuroendocrine regulation of energy balance. Obesity in the U.S. is an epidemic with 65% of adults and 25% of children being overweight or obese. This project began with the identification of a novel form of monogenic obesity in a child with a balanced translocation disrupting a gene called SIM1. The Sim1 heterozygous knock out mouse is also hyperphagic, and obese. SIM1 is expressed in the hypothalamus, mostly in the paraventricular nucleus. We aim to define the molecular function of SIM1 in feeding regulation as it relates to known hypothalamic pathways. Sim1 heterozygous mice have the phenotypic constellation suggested to be a hallmark of defective melanocortin signaling, namely hyperphagia, obesity, increased length, and a sensitivity to high fat. This constellation is not only found in melanocortin-4 receptor-/- (mc4r-/-) mice and Agouti Yellow mice (Ay) but also in mice deficient in bdnf (brain derived neurotrophic factor) and its receptor. We showed that unlike mc4r-/- mice, Sim1 heterozygotes have a normal energy expenditure. They are resistant to the anorectic effect of MTII, a potent Mc4r agonist, but not its effect of energy expenditure. They fail to activate PVN neurons in response to MTII, suggesting a divergence between feeding and energy expenditure, with Mc4r neurons in the PVN regulating feeding and Mc4r neurons elsewhere in the CNS regulating energy expenditure. We will use Sim1 GFP mice to examine colocalization of Sim1, MTII induced c-fos, and oxytocin. We will use various molecules to attempt to rescue the Sim1 obesity phenotype. We will attempt to identify gene targets of SIM1 after knocking down SIM1 expression in a hypothalamic cell line and performing a gene array. The anticipated outcome of these experiments will place Sim1 in known molecular and physiologic pathways that regulate food intake. These results could lead to new targets for pharmacologic agents to prevent or treat obesity and its sequelae such as type 2 diabetes mellitus and coronary artery disease, major public health threats in the United States and other developed nations. The relevance of this project to public health is that it studies obesity, a major public health concern. We are trying understand how the brain regulates our eating behavior. We study a gene that was found to cause morbid obesity in a girl. We are using a mouse model of this gene to understand how it causes obesity.